A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis

Keel, Siobán; Doty, Raymond T.; Yang, Zhilin; Quigley, John G.; Chen, Jing; Knoblaugh, Sue E.; Kingsley, Paul D.; Domenico, Ivana De; Vaughn, Michael B.; Kaplan, Jerry; Palis, James; Abkowitz, Janis L.

doi:10.1126/science.1151133

Cited by 342 publications

(438 citation statements)

References 22 publications

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“…Decreased iron availability likely results in more effective erythropoiesis, as less iron is available during erythroid development to generate free heme or α-globin precipitates, factors associated with shortened rbc survival. Previously presented data demonstrate that the absence of heme-regulated inhibitor (HRI) kinase, which controls Hb synthesis (25), exacerbates the β-thalassemia phenotype (26), while lack of heme exporter feline leukemia virus subgroup C cellular receptor (FLVCR), which controls heme export (27), impairs rbc formation (28). These observations, along with our new data, suggest that an excess of iron and/or heme (in addition to α-globin) in erythroid cells might be deleterious to erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Gardenghi¹,

Ramos²,

Marongiu³

et al. 2010

J. Clin. Invest.

205

216

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Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

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Section: Discussionmentioning

confidence: 99%

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Gardenghi¹,

Ramos²,

Marongiu³

et al. 2010

J. Clin. Invest.

205

216

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“…74,75 Another potential mechanism, depicted in Figure 3B, is that defective maturation of ribosomal subunits could delay translation of globin genes, resulting in a relative excess of free heme, which would also lead to erythroid-specific apoptosis and anemia. 76 Both of these potential mechanisms are discussed in more detail in "Ribosomal haploinsufficiency in human disease." Alternate mechanisms include pathogenic functions for the aberrantly accumulated ribosomal precursors and aberrant translation by defective ribosomes.…”

Section: Cellular Consequences Of Ribosomal Haploinsufficiencymentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

691

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. On the other hand, the downregulation of HCP-1, a folate transporter and heme carrier protein that transports iron out of the endosome, may impair iron recycling and contribute to greater iron sequestration within inflammatory macrophages [14].…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN-c (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin-mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions. Key words: Immune system . Iron . Polarized macrophages IntroductionMacrophages play a critical role in body iron homeostasis by recovering iron from old red blood cells and returning it to the circulation for binding to transferrin, which delivers the metal to the cells that need it for various functions, thus contributing more than 80% to daily iron turnover [1][2][3].Iron retention in the reticuloendothelial system is the main response of body iron homeostasis to inflammation and is regarded as a host's attempt to withhold iron from the invading pathogens [4]. This restricts iron availability for erythroid progenitor cells and may contribute toward causing the common condition of inflammation-related anaemia [1,5,6]. Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. O...

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A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis

Cited by 342 publications

References 22 publications

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Ribosomopathies: human disorders of ribosome dysfunction

Differential regulation of iron homeostasis during human macrophage polarized activation

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